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Consensus Virtual Screening Identified [1,2,4]Triazolo[1,5‐ b ]isoquinolines As MELK Inhibitor Chemotypes
Author(s) -
Rácz Anita,
Palkó Roberta,
Csányi Dorottya,
Riedl Zsuzsanna,
Bajusz Dávid,
Keserű György M.
Publication year - 2022
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100569
Subject(s) - virtual screening , chemotype , computational biology , enzyme , stereochemistry , in vitro , chemistry , biology , combinatorial chemistry , biochemistry , drug discovery , essential oil , chromatography
Maternal Embryonic Leucine‐zipper Kinase (MELK) is a current oncotarget involved in a diverse range of human cancers, with the usage of MELK inhibitors being explored clinically. Here, we aimed to discover new MELK inhibitor chemotypes from our in‐house compound library with a consensus‐based virtual screening workflow, employing three screening concepts. After careful retrospective validation, prospective screening and in vitro enzyme inhibition testing revealed a series of [1,2,4]triazolo[1,5‐ b ]isoquinolines as a new structural class of MELK inhibitors, with the lead compound of the series exhibiting a sub‐micromolar inhibitory activity. The structure‐activity relationship of the series was explored by testing further analogs based on a structure‐guided selection process. Importantly, the present work marks the first disclosure of the synthesis and bioactivity of this class of compounds.